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Published online 12 March 2004

Nucleic Acids Research, 2004, Vol. 32, No. 5 1696-1709
© 2004 Oxford University Press

Functional interactions between alternatively spliced forms of Pax6 in crystallin gene regulation and in haploinsufficiency

Bharesh K. Chauhan, Ying Yang, Kveta Cveklová and Ales Cvekl*

Department of Ophthalmology and Visual Sciences and Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA

*To whom correspondence should be addressed. Tel: +1 718 430 3217; Fax: +1 718 430 8778; Email: cvekl{at}aecom.yu.edu

Pax6 is essential for development of the eye, olfactory system, brain and pancreas. Haploinsufficiency of Pax6 causes abnormal eye development. Two forms of Pax6 protein, PAX6 and PAX6(5a), differ in a 14 amino acid insertion encoded by an alternatively spliced exon 5a in the N-terminal DNA-binding paired domain (PD), and they are simultaneously expressed. Here, we show that PAX6 and PAX6(5a) together synergistically activate transcription from promoters recognized by Pax6 PD and PD5a, but not by their homeodomain. This synergism promotes activation of transcription by c-Maf and MafA on the {alpha}B-crystallin promoter, and is required for transcriptional co-activation by RARß/RXRß and PAX6/PAX6(5a) on the {gamma}F-crystallin promoter. To determine the role of this synergism in haploinsufficiency, we tested four human missense (G18W, R26G, G64V and R128C) and one nonsense (R317X) mutants, with reporters driven by Pax6 PD consensus binding sites and the {alpha}B-crystallin promoter. The simultaneous activity of Pax6 proteins [PAX6, mutated PAX6, PAX6(5a) and mutated PAX6(5a)] modeling haploinsufficiency yielded results not predicted by properties of individual PAX6 or PAX6(5a). Taken together, these results indicate that complex ocular phenotypes due to Pax6 haploinsufficiency originate, at least partially, from functional interactions between alternatively spliced PAX6 and PAX6(5a) variants and other factors, e.g. MafA/c-Maf.


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